Benefit Risk Analysis

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EU PV Changes to PSURs & Strategies for Benefit-Risk Analysis
Hemendra Misra MD, MPH, MSc, Senior Director, Product Risk Management William C. Maier MPH, PHD, Chief Scientific Officer 29 May 2013
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Mapi 2013, All rights reserved
Hemendra Misra MD, MPH, MSc

Senior Director, Product Risk Management GERMANY Pharmacovigilance Physician with seventeen years of international work experience Nine years of Industry experience (Pharma & CRO) - Medical Monitor, Drug Safety Physician, Safety Expert, Risk Management Expert Took a lead scientific, commercial and organizational role in the development of safety and risk management services for both new and existing pharmaceutical company clients
Medical practice includes positions in hospitals in India and with Medecines Sans Frontieres (Doctors Without Borders)
Public health experience: Consultant for a WHO Anti-Malaria program in India Member of the STB SARS Containment Team in Singapore Medical Officer for the Health Promotion Board in Singapore
William C. Maier, PhD

Chief Scientific Officer UK Over 20 years experience in biopharmaceutical industry with specialty in the design, analysis, and interpretation for epidemiology & observational studies Editor PharmacoEPI and Risk Management Newsletter www.prmnewsletter.org Frequent international speaker on Epidemiology, Health Technology Assessment, Drug Safety and Risk Management Previously Senior Director of Epidemiology at GSK and Elan Pharmaceuticals EMEA Working Group Member Specialties Respiratory, Endocrinology, Gastrointestinal, Autoimmune, Vaccines, Oncology
Network of Pharmacoepidemiology Centres in EU EnCEPP Project
Agenda
Topic
The new PSUR and its requirements Challenges in preparing the PSUR
Presenter
Hemendra Misra
Hemendra Misra
Strategies for presenting the benefit-risk analysis Summary
Will Maier
Hemendra Misra
Questions
Hemendra Misra & Will Maier
The new PSUR and its Section 1 requirements
The new PSUR - Definition

Periodic safety update reports (PSURs) are pharmacovigilance documents intended to provide an evaluation of the risk-benefit balance of a medicinal product. They shall be submitted by marketing authorisation holders at defined time points during the post-authorisation phase.
Legal basis for the PSUR

Regulation (EU) No 1235/2010 Directive 2010/84/EU Commission Implementing Regulation (EU) No 520/2012
Guidance on scope, objectives, format and content of the PSUR

European Medicines Agency (EMA) Guideline on good pharmacovigilance practices (GVP) Module VII Periodic safety update report
based on those for the Periodic Benefit Risk Evaluation Report (PBRER) described in the ICH-E2C(R2) guideline
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Structure of the PSUR

Part I: Title page including signature Part II: Executive Summary Part III: Table of Contents 1. Introduction 2. Worldwide marketing authorisation status 3. Actions taken in the reporting interval for safety reasons 4. Changes to reference safety information 5. Estimated exposure and use patterns 5.1. Cumulative subject exposure in clinical trials 5.2. Cumulative and interval patient exposure from marketing experience 6. Data in summary tabulations 6.1. Reference information 6.2. Cumulative summary tabulations of serious adverse events from clinical trials 6.3. Cumulative and interval summary tabulations from post-marketing data sources 7. Summaries of significant findings from clinical trials during the reporting interval 7.1. Completed clinical trials 7.2. Ongoing clinical trials 7.3. Long-term follow-up 7.4. Other therapeutic use of medicinal product 7.5. New safety data related to fixed combination therapies 8. Findings from non-interventional studies 9. Information from other clinical trials and sources 9.1. Other clinical trials 9.2. Medication errors 10. Non-clinical Data
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Structure of the PSUR (2)

11. Literature 12. Other periodic reports 13. Lack of efficacy in controlled clinical trials 14. Late-breaking information 15. Overview of signals: new, ongoing or closed 16. Signal and risk evaluation 16.1. Summaries of safety concerns 16.2. Signal evaluation 16.3. Evaluation of risks and new information 16.4. Characterisation of risks 16.5. Effectiveness of risk minimisation (if applicable) 17. Benefit evaluation 17.1. Important baseline efficacy and effectiveness information 17.2. Newly identified information on efficacy and effectiveness 17.3. Characterisation of benefits 18. Integrated benefit-risk analysis for authorised indications 18.1. Benefit-risk context Medical need and important alternatives 18.2. Benefit-risk analysis evaluation 19. Conclusions and actions 20. Appendices to the PSUR
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Key Changes to the PSUR

Objective, format, content, timelines New section on Benefit-risk evaluation New section on Safety Signals No routine line-listings required No PSURs required for certain category of products
generic medicinal products well-established use medicinal products homeopathic medicinal products traditional herbal medicinal products
Operational aspects
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Potential sources of information for the PSUR (efficacy, effectiveness, safety information)
non-clinical studies spontaneous reports (e.g. on the marketing authorisation holders safety database) active surveillance systems (e.g. sentinel sites) investigations of product quality product usage data and drug utilisation information clinical trials, including research in unauthorised indications or populations observational studies, including registries patient support programs systematic reviews and meta-analysis marketing authorisation holders sponsored websites published scientific literature or reports from abstracts, including information presented at scientific meetings unpublished manuscripts licensing partners, other sponsors or academic institutions and research networks competent authorities (worldwide)
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Overview of Signals
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Safety Signal Evaluation

source or trigger of the signal background relevant to the evaluation
method(s) of evaluation, including data sources, search criteria (where applicable, the specific MedDRA terms (e.g. PTs, HLTs, SOCs, etc.) or Standardised MedDRA Queries (SMQs) that were reviewed), and analytical approaches
results - a summary and critical analysis of the data considered in the signal evaluation; where integral to the assessment, this may include a description of a case series or an individual case (e.g. an index case of well documented agranulocytosis or Stevens Johnson Syndrome) discussion conclusion
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The EU single assessment

In order to increase the shared use of resources between competent authorities in Member States, a single assessment of PSURs shall be performed in the EU A single EU PSUR assessment provides a mechanism for evaluating the totality of available data on the benefits and risks of an active substance or combination of active substances. The EU single assessment is the assessment of PSURs for medicinal products
subject to different marketing authorisations containing the same active substance or the same combination of active substances whether or not held by the same marketing authorisation holder and for which the frequency and dates of submission of PSUR have been harmonised in the list of EU reference dates
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European Union reference date (EURD)

This corresponds to the date of the first or the earliest known date of the marketing authorisation in the Union of a medicinal product containing the active substance or combination of active substances EU reference dates list - a list of active substances and combinations of active substances sorted in alphabetical order, for which PSURs shall be submitted in accordance with the EU reference dates and frequencies determined by the Committee for Medicinal Products for Human Use (CHMP) and the Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh) following consultation with the Pharmacovigilance and Risk Assessment Committee (PRAC) The EURD list is available on the web portal of EMA
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Frequency of the PSUR

The MAH is required to submit PSURs once a medicinal product is authorised in the EU, even if it is not marketed If the active substance contained in the medicinal product is not listed on the EURD list, the MAH should continue to submit PSUR according to the condition in the MA if any, otherwise according to the standard submission cycle:
Immediately upon request At least 6 monthly after authorisation and until the placing on the market At least 6 monthly for the first two years after being placed on the market Annually for the subsequent two years Thereafter at three-yearly intervals
The EURD list is binding from DLPs as of 1st April 2013
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Timelines for submission

Marketing authorisation holders should submit to the Agency PSURs within 70 or 90 days from the data lock point:
within 70 calendar days of the data lock point (day 0) for PSURs covering intervals up to 12 months (including intervals of exactly 12 months); and within 90 calendar days of the data lock point (day 0) for PSURs covering intervals in excess of 12 months; the timeline for the submission of ad hoc PSURs requested by competent authorities will be normally specified in the request, otherwise the ad hoc PSURs should be submitted within 90 days of the data lock point.
Additional timelines provided due to the increased complexity of the PSUR
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Interim Arrangements for submission of PSURs

Before the Agencys PSUR repository is in place
MAHs shall submit the PSURs to all competent authorities in Member States in which the medicinal products are authorised For the substances or combination of active substances subject to a single assessment or for which an EU reference date has been established, the PSURs should be also sent to the Agency The competent authorities in Member States requirements for the submission of PSURs during this transitional period are published in the Agency web-site
From 12 months after the functionalities of the repository have been established and have been announced by the Agency, the marketing authorisation holders shall submit the PSURs electronically to the Agency Once the structured electronic format ePSUR, based on content agreed in the ICH-E2C(R2), becomes available, marketing authorisation holders will have the possibility to submit PSURs and related documents automatically via an electronic gateway
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Evaluation of the PSUR

Day Day 0 Action Start of the procedure according to the published timetable
Day 60
PRAC Rapporteurs preliminary assessment report
Day 90 Day 105
MAH and PRAC members comments PRAC Rapporteurs updated assessment report (if necessary)
Day 120
PRAC recommendation adoption with the final PRAC assessment report CHMP opinion / CMDh position
Day 134
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Transparency
Publication of PSUR-related documents on the European medicines and national medicines web-portals
list of EU reference dates and frequency of submission of PSURs final assessment conclusions of the adopted assessment reports PRAC recommendations including relevant annexes CMDh position including relevant annexes and where applicable, detailed explanation on scientific grounds for any differences with the PRAC recommendations CHMP opinion including relevant annexes and where applicable, detailed explanation on scientific grounds for any differences with the PRAC recommendations European Commission decision
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Quality Management System at MAH

Specific quality system procedures and processes shall be in place in order to ensure the update of product information Responsibility of the marketing authorisation holder to check regularly the list of EU reference dates and frequency of submission published in the European medicines web-portal to ensure compliance with the PSUR reporting requirements for their medicinal products Systems should be in place to schedule the production of PSURs as per regulatory requirements and ad hoc requests For those medicinal products where the submission of an RMP is not required, the marketing authorisation holder should maintain on file a specification of important identified risks, important potential risks and important missing information in order to support the preparation of the PSURs The marketing authorisation holder should have procedures in place to follow the requirements established by the Agency for the submission of PSURs. The QPPV shall be responsible for the establishment and maintenance of the pharmacovigilance system
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Challenges in preparing the Section 1 PSUR
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New document, new requirements

Creation of a new process for producing the report based on new and additional data required from different stakeholders New template
Modular structure E-submissions
Training of resources
Identification of concerned Departments Identification of relevant personnel Internal/External training
Maintaining compliance
Documentation Internal/external audits
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Multi-functional involvement
Roles, responsibilities and timelines for gathering the data required
Clear leadership Early planning Availability of personnel Timely contributions by stakeholders Peak workloads Appropriate oversight if you consider outsourcing
Close collaboration
Commitment by different stakeholders Regular communication Agreement on conclusions
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Signal Management Process

Signal Detection process
Documented, compliant process and system
Timely follow-up of signals

Time & Resource constraints Training
Overview of signals
Clear ownership Up-to-date information
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No globally accepted standards of benefit-risk methodology

New requirement Wide variation exists in the industry Qualitative or Quantitative?
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Strategies for presenting the benefit-risk analysis
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GVP Definition: Risk-benefit balance

An evaluation of the positive therapeutic effects of the medicinal product in relation to the risks [DIR 2001/83/EC Art 1(28a)] (i.e. any risk relating to the quality, safety or efficacy of the medicinal product as regards patients health or public health [DIR 2001/83/EC Art 1(28)]).
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GVP Module Guidance - Provide a clear explanation of the methodology and reasoning used to develop the benefit-risk evaluation:
The assumptions, considerations, and judgement or weighting that support the conclusions of the benefitrisk evaluation should be clear. If a formal quantitative or semi-quantitative assessment of benefit-risk is provided, a summary of the methods should be included. Economic considerations (e.g. cost-effectiveness) should not be considered in the benefit-risk evaluation.
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ICH EC2 Benefit:Risk Assessment Method

Only key benefits and risks considered in the evaluation should be specified Context of use of the medicinal product Benefit - consider its nature, clinical importance, duration, and generalizability, as well as evidence of efficacy in non-responders to other therapies and alternative treatments. Risk - consider its clinical importance, e.g., nature of toxicity, seriousness, frequency, predictability, preventability, reversibility, impact on patients, and whether it arose from off-label use, a new use, or misuse.
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ICH EC2 Benefit:Risk Assessment Method (2)

Strengths, weaknesses, and uncertainties of the evidence should be considered when formulating the benefit-risk evaluation. Explanation of the methodology and reasoning used to develop the benefit-risk evaluation Comment on the feasibility of expressing benefits and risks in such a way as to facilitate their comparison. If a formal quantitative assessment of benefit-risk is provided, a summary of the methods should be included. Economic considerations (e.g., cost-effectiveness) should not be considered in the benefit-risk evaluation.
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Systematic Benefit and Risk Assessment used to Build Development and Post-Marketing Strategy (2002)
Disease
Epidemiology disease info Target & actual use Expected Actual use pop.co-morbidities Pre-clin data, Competitors, Previous experience, + Phase I-II data regulatory knowledge
Increased awareness in target population Actual use population + Post-marketing experience + Postmarketing experience
Benefit Risk
+ Phase II-III data
Pre-clin data, Competitors, + Phase I-II data, Previous experience, Health regulatory knowledge outcomes
+ Phase II-III data, health economics
Profile
Disease specific B:R profile (& model)
B:R profile based on product facts (reality profile)
Strategy
Development Activities
Post-Marketing Plan
Commit to P3 decision point File decision Mapi 2013, All rights reserved point
Candidate selection
FTIH decision point
Ph 2b decision point
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Eichler (EMA) DIA Annual Meeting June 2009
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Benefit-risk methodology project (2010)
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Qualitative Approaches
A generic qualitative approach of eight steps for decision making, PrOACT, is presented as it might apply to decision-making by regulators, followed by descriptions of three approaches currently under development: PhRMA BRAT, CMR CASS study and FDA BRF.
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PrOACT
PROBLEM. Determine the nature of the problem and its context (approve/disapprove, restrict); OBJECTIVES. Identify objectives that indicate the overall purposes to be achieved (e.g., maximise favourable effects, minimise unfavourable effects), and develop criteria against which the alternatives can be evaluated ALTERNATIVES. Identify the options (actions about a medicinal product or the products themselves) to be evaluated CONSEQUENCES. describe how the alternative would perform on the criteria TRADE-OFFS. Assess the balance between favourable and unfavourable effects. UNCERTAINTY. Consider how the balance between favourable and unfavourable effects would change by taking account of the uncertainty associated with the consequences. RISK. Judge the relative importance of the Agencys risk attitude for this medicinal product and how risk would be LINKED DECISIONS. Consider the consistency of this decision with similar past decisions, and assess whether taking this decision could impact future decisions
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Quantitative B-R Methods MULTI-CRITERIA DECISION ANALYIS (MCDA)
A sub-discipline of operations research that explicitly considers multi-criteria in decision-making environments.

7 steps that form a conceptual framework.
Establish the decision context. Identify the options to be appraised. Identification of the benefit and risk criteria & organization into a value tree. Assessment of expected performance of each option against criteria. Assign weights for each criterion to reflect relative importance. Calculation of weighted scores at each level in hierarchy and overall. Examination of results and sensitivity analysis.
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Current Scenario:
Systematic Structured Benefit:Risk Assessment is becoming part of regulatory requirements in EU, USA, Japan Qualitative approaches generally similar Quantitative approaches - limited by ability to compare dissimilar health benefits and risks MCDA provides modelling technique to compare different benefits and risks, provides tools for sensitivity analysis EMA and other EU regulatory agencies working to understand decision making context
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Summary
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Summary
There has been a paradigm shift in the new format and content of the PSUR, legally required in the EU from Jan 2013 and accepted in the other ICH regions - US and Japan The sections on signal detection and benefit-risk analysis present new challenges for the preparation of the PSUR
If a formal quantitative or semi-quantitative assessment of benefit-risk is provided, a summary of the methods should be included
The assumptions, considerations, and judgement or weighting that support the conclusions of the benefit-risk evaluation should be clear
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Questions
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Thank you for attending!
Hemendra Misra: hmisra@mapigroup.com Will Maier: wmaier@mapigroup.com
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Global Head Office: 27 rue de la Villette | 69003 Lyon | France | Tel: +33 (0) 4 72 13 66 93 US Head Office: 2343 Alexandria Drive | Suite 100 | Lexington | KY 40504 | USA | Tel +1 859 223 4334 contactus@mapigroup.com | www.mapigroup.com
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Webcast Notes

EU PV Changes to PSURs & Strategies for Benefit-Risk Analysis

Mapi 2013, All rights reserved

Hemendra Misra MD, MPH, MSc

Mapi 2013, All rights reserved

William C. Maier, PhD

Network of Pharmacoepidemiology Centres in EU EnCEPP Project

Mapi 2013, All rights reserved

Strategies for presenting the benefit-risk analysis Summary

Hemendra Misra & Will Maier

Mapi 2013, All rights reserved

The new PSUR and its Section 1 requirements

Mapi 2013, All rights reserved

The new PSUR - Definition

Mapi 2013, All rights reserved

Legal basis for the PSUR

Guidance on scope, objectives, format and content of the PSUR

Mapi 2013, All rights reserved

Structure of the PSUR

Mapi 2013, All rights reserved

Structure of the PSUR (2)

Mapi 2013, All rights reserved

Key Changes to the PSUR

Mapi 2013, All rights reserved

Mapi 2013, All rights reserved

Mapi 2013, All rights reserved

Safety Signal Evaluation

Mapi 2013, All rights reserved

The EU single assessment

Mapi 2013, All rights reserved

European Union reference date (EURD)

Mapi 2013, All rights reserved

Frequency of the PSUR

The EURD list is binding from DLPs as of 1st April 2013

Mapi 2013, All rights reserved

Timelines for submission

Additional timelines provided due to the increased complexity of the PSUR

Mapi 2013, All rights reserved

Interim Arrangements for submission of PSURs

Mapi 2013, All rights reserved

Evaluation of the PSUR

PRAC Rapporteurs preliminary assessment report

Day 90 Day 105

Mapi 2013, All rights reserved

Mapi 2013, All rights reserved

Quality Management System at MAH

Mapi 2013, All rights reserved

Challenges in preparing the Section 1 PSUR

Mapi 2013, All rights reserved

New document, new requirements

Mapi 2013, All rights reserved

Mapi 2013, All rights reserved

Signal Management Process

Timely follow-up of signals

Mapi 2013, All rights reserved

No globally accepted standards of benefit-risk methodology

Mapi 2013, All rights reserved

Strategies for presenting the benefit-risk analysis

Mapi 2013, All rights reserved

GVP Definition: Risk-benefit balance

Mapi 2013, All rights reserved

Mapi 2013, All rights reserved

ICH EC2 Benefit:Risk Assessment Method

Mapi 2013, All rights reserved